Curcumin is the major curcuminoid of the Indian curry spice turmeric. Curcumin is known for its anti-oxidant, anti-arthritic, anti-amyloid and anti-inflammatory properties. In addition, over recent years, activity of curcumin against various types of cancer have been widely documented (Rao C. V. et al, Cancer Res. 55, 259-266, 1995, Kawamori et al, Cancer Res. 59, 597-601, 1999).
While curcumin exhibits promising anti-cancer and/or anti-inflammatory properties, one of its major drawbacks relates to its absorption, distribution and excretion in vivo. It has been described that blood levels of curcumin are always low after per os (oral) administration while they rise through intravenous injection. Besides that, it has been described that curcumin is totally metabolised in half an hour and that curcumin does not induce toxicity (Wahlström B. et al, Acta pharmacol. et toxicol. 43, 86-92, 1978; Pan M. H. et al, Drug Metabolism and Disposition, 27, 486-494, 1999, Ireson C. et al, Cancer Res. 61, 1058-1064, 2001).
Although the level of activity found for curcumin and curcuminoid derivatives was and continues to be of high interest, this administered material does have significant deficiencies which indicates the continuing need for curcumin-complexes with improved properties. In the first place, curcumin was found to be insoluble in the majority of usual solvents. In addition, the plasma concentrations of curcumin after per os administration are either undetectable or very weak whatever the dosage level. Also, it seems that curcumin is quickly reduced (tetrahydrocurcumin, hexahydrocurcumin, hexahydrocurcuminol) and/or transformed (glucuronides or sulphates) in vivo. Thus, while curcumin and curcuminoid derivatives show significant biological activity, they do not have physico-chemical properties suitable for further clinical development. The same shortcomings were observed for cyclodextrin complexes of curcuminoid derivatives as for salts of curcuminoid derivatives.
In addition, although the pre-clinical activity of anti-proliferative agents such as curcumin itself or curcuminoid derivatives against certain forms of cancers can be shown, improvement in tumour response rates, duration of response, decrease of toxicity and ultimately patient survival are still sought.
Clinical data has furthermore indicated that patients displaying pulmonary inflammatory diseases have a higher incidence of developing lung tumours. This suggests that a persistent pulmonary inflammation might alter the organ's properties to develop tumours, although the exact mechanisms connecting chronic inflammatory processes to cancer are not yet well known. Until today, no treatment for precancerous lesions in the lungs exists. There is also no treatment available which can stop or slow down the formation of lung cancer in patients displaying an inflammatory disease in the airways.
There is therefore an urgent need for identifying new active molecules displaying a potential interest for the treatment of inflammatory, precancerous or cancer diseases.
There is also a need in the art for improving the efficacy of anti-proliferative and anti-inflammatory treatments in humans and animals by providing suitable combinations of new drugs with conventional anti-neoplastic and/or anti-inflammatory agents.
In view of the above-mentioned shortcomings of most of the agents used today in hospitals to treat cancer patients or patients with inflammatory disease, of known curcumin and curcuminoid derivatives, of salts of curcuminoid derivatives and of cyclodextrin complexes of curcuminoid derivatives, there is a need in the art for new curcumin-derived compounds having enhanced physico-chemical properties and demonstrating a more promising activity/side effects balance.
The aim of the present invention was therefore to provide a new potential anti-proliferative and/or anti-inflammatory agent that is suitable for per os administration. Simultaneously, said new agents were evaluated for their ability to modulate pulmonary inflammation and/or lung cancer progression through trans-tracheal administration (e.g. inhalation).
Our findings suggest that new curcumin-derivatives of the present invention are interesting candidates for therapy against both proliferative and/or inflammatory disorders. Especially the increased solubility and prolonged stability of the curcumin-derivatives according to the invention and their surprising activity via per os administration is very interesting and unexpected.